A. Background Regarding Cyclosporine
The compositions of the invention comprise a cyclosporine. Cyclosporines are a large class of peptide compounds having pharmaceutical utility, for example immunosuppressant, anti-inflammatory, and/or anti-parasitic activity and/or activity in abrogating tumor resistance to anti-neoplastic or cytostatic drug therapy. Cyclosporine is a cyclic non-ribosomal polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the ascomycete fungus Beauveria nivea. The cyclosporines include, for example, naturally occurring fungal metabolites, such as the cyclosporine A, B, C, D and G, as well as a wide variety of synthetic and semi-synthetic cyclosporines, for example the dihydro- and iso-cyclosporines.
Cyclosporines have been described in, for example, U.S. Pat. Nos. 5,756,450 for “Water Soluble Monoesters as Solubisers for Pharmacologically Active Compounds and Pharmaceutical Excipients and Novel Cyclosporine Galenic Forms;” 5,759,997 for “Cyclosporin Galenic Forms; 5,977,066 for “Cyclosporin Galenic Forms”; 6,239,124 for “Pharmaceutical Compositions for the Treatment of Transplant Rejection or Autoimmune or Inflammatory Conditions Comprising Cyclosporin A and 40-O-(2-hydroxyethyl)-rapamycin;” 6,262,022 for “Pharmaceutical Compositions Containing Cyclosporin as the Active Agent;” 6,306,825 for “Cyclosporin Galenic Forms;” 6,432,445 for “Pharmaceutical Capsules Comprising a Cyclosporin;” 6,455,518 for “Pharmaceutical Compositions for the Treatment of Transplant Rejection or Autoimmune or Inflammatory Conditions Comprising Cyclosporin A and 40-0-(2-hydroxyethyl)-rapamycin;” 6,468,968 for “Cyclosporin Galenic Forms”; 6,475,519 for “Oil-free Pharmaceutical Compositions Containing Cyclosporin A;” 6,486,124 for “Cyclosporin Compositions and Processes Therefor;” 6,582,718 for “Cyclosporin Compositions;’ 6,620,325 for “Purification Process for Cyclosporin;” and 6,723,339 for “Oil-free Pharmaceutical Compositions Containing Cyclosporin A.”
Cyclosporine has been demonstrated to suppress some humoral immunity and, to a greater extent, cell-mediated reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft versus host disease in many animal species for a variety of organs. It has been used post-allogenic organ transplant to reduce the activity of the patient's immune system to lower the risk of organ rejection in the case of transplants of skin, heart, kidney, lung, pancreas, bone marrow and small intestine.
Apart from transplant medicine, cyclosporine is also used in treating psoriasis and rheumatoid arthritis and related diseases, although only in severe cases, and has been investigated for use in treating many other autoimmune disorders. It is often taken in conjunction with corticosteroids. More recently, cyclosporine has been used successfully in treating patients suffering from ulcerative colitis.
Experimental evidence suggests that the effectiveness of cyclosporine is due to specific and reversible inhibition of immunocompetent lymphocytes in the G0- or G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2 or T-cell growth factor (TCGF). Cyclosporine is thought to bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophylin inhibits calcineurin, which under normal circumstances is responsible for activating the transcription of interleukin-2. It also inhibits lymphokine production and interleukin release and therefore leads to a reduced function of effector T-cells. No functional effects on phagocytic (changes in enzyme secretions not altered, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) or tumor cells (growth rate, metastasis) can be detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.
Chemically, cyclosporine is designated as [R—[R*,R*-(E)]]-cyclic (L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-(alpha)-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl). The molecular formula of cyclosporine is C62H111N11O12 with a molecular weight of 1202.63. The chemical structure of cyclosporine (also known as cyclosporin A) is:
The drug is sold by Novartis under the brand names SANDIMMUNE® and NEORAL®. NEORAL® and SANDIMMUNE® differ in that NEORAL® has increased bioavailability compared to SANDIMMUNE®. Adjunct therapy with adrenal corticosteroids is recommended. Generic cyclosporine drugs have been produced by companies such as Sangstat, Abbott Laboratories and Gengraf. A topical emulsion of cyclosporine for treating keratoconjunctivitis sicca has been marketed under the trade name RESTASIS®.
The absorption of cyclosporine from the gastrointestinal tract is incomplete and variable. Peak concentrations (Cmax) in blood and plasma are achieved at about 3.5 hours. Cmax and area under the plasma or blood concentration/time curve (AUC) increase with the administered dose; for blood the relationship is curvilinear (parabolic) between 0 and 1400 mg. Cmax is approximately 1.0 ng/mL/mg of dose for plasma and 2.7-1.4 ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous infusion, the absolute bioavailability of the oral solution is approximately 30% based upon the results in 2 patients.
Cyclosporine is distributed largely outside the blood volume. In blood the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the uptake by leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins.
Cyclosporines are of high therapeutic value for the prevention of organ transplant rejection, and the treatment of autoimmune diseases, such as psoriasis and rheumatoid arthritis. However, cyclosporines present highly specific difficulties in relation to administration including in particular problems of stability, drug bioavailability, and variability in inter- and intra-patient dose response. In addition, because cyclosporine is practically insoluble in water, conventional cyclosporine tablets dissolve the drug in potentially toxic co-solvents, for example, propylene glycol. The daily dose of cyclosporine must be given in two divided doses, and should be administered on a consistent schedule with regard to time of day and in relation to meals.
Thus, there is a need in the art for cyclosporine compositions which overcome these and other problems associated with their use. The present invention then relates to a composition for the controlled release of a cyclosporine. The present invention also relates to a nanoparticulate formulation of cyclosporine having improved bioavailability. The present invention also relates to a composition for the controlled release of a nanoparticulate cyclosporine. In particular, the present invention relates to controlled release compositions that in operation deliver a cyclosporine in a pulsatile or in a constant zero order manner or an immediate release nanoparticulate composition with improved bioavailability. The present invention further relates to solid oral dosage forms containing such a controlled release or immediate release composition.
B. Background Regarding Nanoparticulate Compositions
Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer. The '684 patent does not describe nanoparticulate compositions of cyclosporines.
Methods of making nanoparticulate compositions are described in, for example, U.S. Pat. Nos. 5,518,187 and 5,862,999, both for “Method of Grinding Pharmaceutical Substances;” U.S. Pat. No. 5,718,388, for “Continuous Method of Grinding Pharmaceutical Substances;” and U.S. Pat. No. 5,510,118 for “Process of Preparing Therapeutic Compositions Containing Nanoparticles.”
Nanoparticulate compositions are also described, for example, in U.S. Pat. Nos. 5,298,262 for “Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;” 5,302,401 for “Method to Reduce Particle Size Growth During Lyophilization;” 5,318,767 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,326,552 for “Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,328,404 for “Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates;” 5,336,507 for “Use of Charged Phospholipids to Reduce Nanoparticle Aggregation;” 5,340,564 for “Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability;” 5,346,702 for “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;” 5,349,957 for “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles;” 5,352,459 for “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;” 5,399,363 and 5,494,683, both for “Surface Modified Anticancer Nanoparticles;” 5,401,492 for “Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;” 5,429,824 for “Use of Tyloxapol as a Nanoparticulate Stabilizer;” 5,447,710 for “Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants;” 5,451,393 for “X-Ray Contrast Compositions Useful in Medical Imaging;” 5,466,440 for “Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;” 5,470,583 for “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;” 5,472,683 for “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” 5,500,204 for “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” 5,518,738 for “Nanoparticulate NSAID Formulations;” 5,521,218 for “Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;” 5,525,328 for “Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” 5,543,133 for “Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles;” 5,552,160 for “Surface Modified NSAID Nanoparticles;” 5,560,931 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” 5,565,188 for “Polyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;” 5,569,448 for “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions;” 5,571,536 for “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;” 5,573,749 for “Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” 5,573,750 for “Diagnostic Imaging X-Ray Contrast Agents;” 5,573,783 for “Redispersible Nanoparticulate Film Matrices With Protective Overcoats;” 5,580,579 for “Site-specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;” 5,585,108 for “Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays;” 5,587,143 for “Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;” 5,591,456 for “Milled Naproxen with Hydroxypropyl Cellulose as Dispersion Stabilizer;” 5,593,657 for “Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;” 5,622,938 for “Sugar Based Surfactant for Nanocrystals;” 5,628,981 for “Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;” 5,643,552 for “Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;” 5,718,388 for “Continuous Method of Grinding Pharmaceutical Substances;” 5,718,919 for “Nanoparticles Containing the R(−)Enantiomer of Ibuprofen;” 5,747,001 for “Aerosols Containing Beclomethasone Nanoparticle Dispersions;” 5,834,025 for “Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;” 6,045,829 “Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” 6,068,858 for “Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;” 6,153,225 for “Injectable Formulations of Nanoparticulate Naproxen;” 6,165,506 for “New Solid Dose Form of Nanoparticulate Naproxen;” 6,221,400 for “Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors;” 6,264,922 for “Nebulized Aerosols Containing Nanoparticle Dispersions;” 6,267,989 for “Methods for Preventing Crystal Growth and Particle Aggregation in Nanoparticle Compositions;” 6,270,806 for “Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions;” 6,316,029 for “Rapidly Disintegrating Solid Oral Dosage Form,” 6,375,986 for “Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate;” 6,428,814 for “Bioadhesive Nanoparticulate Compositions Having Cationic Surface Stabilizers;” 6,431,478 for “Small Scale Mill;” and 6,432,381 for “Methods for Targeting Drug Delivery to the Upper and/or Lower Gastrointestinal Tract,” all of which are specifically incorporated by reference. In addition, U.S. Patent Application No. 20020012675 A1, published on Jan. 31, 2002, for “Controlled Release Nanoparticulate Compositions,” describes nanoparticulate compositions, and is specifically incorporated by reference.
Amorphous small particle compositions are described, for example, in U.S. Pat. Nos. 4,783,484 for “Particulate Composition and Use Thereof as Antimicrobial Agent;” 4,826,689 for “Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds;” 4,997,454 for “Method for Making Uniformly-Sized Particles From Insoluble Compounds;” 5,741,522 for “Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods;” and 5,776,496, for “Ultrasmall Porous Particles for Enhancing Ultrasound Back Scatter.”
Because cyclosporine is practically insoluble in water, significant bioavailability can be problematic. There is a need in the art for nanoparticulate cyclosporine formulations which overcome this and other problems associated with the use of cyclosporine in the prevention and treatment of organ transplant rejection and autoimmune diseases such as psoriasis, rheumatoid arthritis, and other related diseases. The present invention satisfies this need.
The present invention then, relates to a nanoparticulate cyclosporine composition for the prevention and treatment of organ transplant rejection and autoimmune diseases such as psoriasis, rheumatoid arthritis, and other related diseases. As described herein, the present invention further relates to controlled release composition comprising such a nanoparticulate cyclosporine.